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The CUL4B-miR-372/373-PIK3CA-AKT axis regulates metastasis in bladder cancer

Abstract

CUL4B, which acts as a scaffold protein in CUL4B-RING ubiquitin ligase (CRL4B) complexes, participates in a variety of biological processes. Previous studies have shown that CUL4B is often overexpressed and exhibits oncogenic activities in a variety of solid tumors. However, the roles and the underlying mechanisms of CUL4B in bladder cancer (BC) were poorly understood. Here, we showed that CUL4B levels were overexpressed and positively correlated with the malignancy of BC, and CUL4B could confer BC cells increased motility, invasiveness, stemness, and chemoresistance. The PIK3CA/AKT pathway was identified as a critical downstream mediator of CUL4B-driven oncogenicity in BC cells. Furthermore, we demonstrated that CRL4B epigenetically repressed the transcription of miR-372/373, via catalyzing monoubiquitination of H2AK119 at the gene cluster encoding miR-372/373, leading to upregulation of PIK3CA and activation of AKT. Our findings thus establish a critical role for the CUL4B-miR-372/373-PIK3CA/AKT axis in the pathogenesis of BC and have important prognostic and therapeutic implications in BC.

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Fig. 1: CUL4B is overexpressed and positively correlated with malignant behavior in BC.
Fig. 2: CUL4B promotes proliferation of BC cells and tumor growth.
Fig. 3: CUL4B promotes migration and invasion of BC cells.
Fig. 4: CUL4B enhances stemness and chemoresistance of BC cells.
Fig. 5: CUL4B positively regulates the PI3K-AKT pathway.
Fig. 6: CUL4B upregulates PIK3CA by repressing miR-372/373.
Fig. 7: CUL4B epigenetically represses transcription of miR-371–373.
Fig. 8: A schematic model showing CUL4B-miR-372/373-PIK3CA-AKT axis contributing to the tumorigenesis of BC.

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Acknowledgements

The authors would like to thank Dr M. Oren for kindly providing psiCHECK2 reporter plasmids containing the 3′UTR wide-type and mutant sequences of PIK3CA. This work was supported by the National Natural Science Foundation of China (81330050 and 81571523 to YG, 31671427 to YZ, 81770660 to GL); the Natural Science Foundation of Shandong Province (ZR2016HZ01 to YG); the Key Research and Development Program of Shandong Province (2016ZDJS07A08 to YG); and Young Scholars Program of Shandong University (to YZ).

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Liu, X., Cui, J., Gong, L. et al. The CUL4B-miR-372/373-PIK3CA-AKT axis regulates metastasis in bladder cancer. Oncogene 39, 3588–3603 (2020). https://doi.org/10.1038/s41388-020-1236-1

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